Dataset Information

Early-onset Parkinsonian behaviors in female Pink1-/- rats.

ABSTRACT: Parkinson disease (PD) is a progressive, neurological disease that affects millions of individuals worldwide. Although instability, rigidity, tremor, and bradykinesia are considered hallmark motor signs of the disease, these are not apparent until mid-to-late stage. In addition to limb motor impairment, individuals with PD also exhibit early-onset speech dysfunction and reduced vocal intelligibility as well as anhedonia and anxiety. Many of these clinical signs vary according to sex in humans with PD. In this study, a translational genetic rat model of early-onset PD (Pink1-/-) was used to address significant gaps in knowledge concerning sex-specific characteristics of limb sensorimotor deficits, vocal motor dysfunction, and changes in affective state. Traditional behavioral tests of limb function, ultrasonic vocalization, anxiety, and anhedonia in the Pink1-/- female rat and wildtype controls were used to test the hypothesis that behavioral performance would significantly differ between genotypes, and that these differences would increase with disease progression (age of the rat). Results demonstrate that Pink1-/- female rats do not exhibit limb sensorimotor deficits but do have significantly reduced intensity (loudness) of vocalizations, and present with anhedonia and anxiety by 8 months of age. Consistent with an early-disease model, Pink1-/- female rats do not exhibit significant decreases in nigrostriatal catecholamines/metabolites, as measured by HPLC. These results are significant in expanding knowledge of early-onset deficits in the female Pink1-/- genetic rat model of PD.

SUBMITTER: Marquis JM

PROVIDER: S-EPMC6824965 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Early-onset Parkinsonian behaviors in female Pink1-/- rats.

Marquis Julia M JM Lettenberger Samantha E SE Kelm-Nelson Cynthia A CA

Behavioural brain research 20190919

Parkinson disease (PD) is a progressive, neurological disease that affects millions of individuals worldwide. Although instability, rigidity, tremor, and bradykinesia are considered hallmark motor signs of the disease, these are not apparent until mid-to-late stage. In addition to limb motor impairment, individuals with PD also exhibit early-onset speech dysfunction and reduced vocal intelligibility as well as anhedonia and anxiety. Many of these clinical signs vary according to sex in humans wi ...[more]

PMID: 31542395

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Project description:BACKGROUND:Parkinson's disease (PD) is a degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft, monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet the underlying pathology mediating these significant voice deficits is unknown. The Pink1-/- rat is a valid model of early-onset PD that presents with analogous vocal communication deficits. Previous work shows abnormal ?-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1-/- rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence the differential expression of genes that interact with Pink1, (2) highlight other key genes that relate to this type of Mendelian PD, and (3) catalog molecular targets that may be important for the production of rat vocalizations. RESULTS:Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats that also mapped to human PD datasets. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. CONCLUSIONS:Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.

Dataset Information

Early-onset Parkinsonian behaviors in female Pink1-/- rats.

Publications

Early-onset Parkinsonian behaviors in female Pink1-/- rats.

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